Not Exactly Pocket Science is a set of shorter write-ups on new stories with links to more detailed takes by the world’s best journalists and bloggers. It is meant to complement the usual fare of detailed pieces that are typical for this blog.
Geneticist sequences own genome, finds genetic cause of his disease
If you’ve got an inherited disease and you want to find the genetic faults responsible, it certainly helps if you’re a prominent geneticist. James Lupski (right) from the Baylor College of Medicine suffers from an incurable condition called Charcot-Marie-Tooth (CMT) disease, which affects nerve cells and leads to muscle loss and weakness.
Lupski scoured his entire genome for the foundations of his disease. He found 3.4 million placed where his genome differed from the reference sequence by a single DNA letter (SNPs) and around 9,000 of these could actually affect the structure of a protein. Lupski narrowed down this list of candidates to two SNPs that both affect the SH3TC2 gene, which has been previously linked to CMT. One of the mutations came from his father and the other from his mother. Their unison in a single genome was the cause of not just Lipson’s disease but that of four of his siblings too.
It’s a great example of how powerful new sequencing technologies can pinpoint genetic variations that underlie diseases, which might otherwise have gone unnoticed. The entire project cost $50,000 – not exactly cheap, but far more so than the sequencing efforts of old. The time when such approaches will be affordable and commonplace is coming soon. But in this case, Lupski’s job was easier because SH3TC2 had already been linked to CMT. A second paper tells a more difficult story.
Jared Roach and David Gallas sequenced the genomes of two children who have two inherited disorders – Miller syndrome and primary ciliary dyskinesia – and their two unaffected parents. We don’t know the genetic causes of Miller syndrome and while the four family genomes narrow down the search to four possible culprits, they don’t close the case.
For great takes on these stories and their wider significance, I strongly recommend you to read Daniel Macarthur’s post on Genetic Future, Mark Henderson’s piece in the Times and Nick Wade’s take in the NYT (even if he does flub a well-known concept). Meanwhile, Ivan Oranksy has an interesting insight into the political manoeuvres that go into publicising two papers from separate journals. And check out this previous story I wrote about how genome sequencing was used to reverse the wrong diagnosis of a genetic disorder.
Male moths freeze females by mimicking bats
Flying through the night sky, a moth hears the sound of danger – the ultrasonic squeak of a hunting bat. She freezes to make herself harder to spot, as she always does when she hears these telltale calls. But the source of the squeak is not a bat at all – it’s a male moth. He is a trickster. By mimicking the sound of a bat, he fooled the female into keeping still, making her easier to mate with.
The evolutionary arms race between bats and moths has raged for millennia. Many moths have evolved to listen out for the sounds of hunting bats and some jam those calls with their own ultrasonic clicks, produced by organs called tymbals. In the armyworm moth, only the males have these organs and they never click when bats are near. Their tymbals are used for deceptive seductions, rather than defence.
Ryo Nakano found that the male’s clicks are identical to those of bats. When the males sung to females, Nakano found that virtually all of them mated successfully. If he muffled them by removing the tymbals, they only got lucky 50% of the time. And if he helped out the muted males by playing either tymbal sounds or bat calls through speakers, their success shot back up to 100%. Nakano says that this is a great example of an animal evolving a signal to exploit the sensory biases of a receiver.
More on bats vs. moths from me
Reference: Biology Letters http://dx.doi.org/10.1098/rsbl.2010.0058
This is the story of a Turkish boy, who became the first person to have a genetic disorder diagnosed by thoroughly sequencing his genome. He is known only through his medical case notes as GIT 264-1 but for the purposes of this tale, I’m going to call Baby T.
At a mere five months of age, Baby T was brought to hospital dehydrated and in poor health. In some ways, this wasn’t surprising. His parents were blood relatives and they had suffered through two miscarriages and the death of one premature baby. Baby T himself was born prematurely at 30 weeks.
Baby T’s family history suggested that he was suffering from a genetic disorder, and his doctor’s best guess was Bartter syndrome. This rare but life-threatening disease is caused by mutations in genes that help to transport ions across the cells of the kidney. Without this ability, babies lose salt, potassium and water and they tend to urinate excessively. The resulting dehydration could kill them if they aren’t regularly topped up with fluids.
The symptoms certainly fit the bill, but his doctors weren’t sure. To play it safe, they took a sample of the boy’s blood and sent it thousands of miles away to a laboratory at Yale University for genetic testing. A thorough scan of the boy’s genome revealed the true cause of his illness – a different genetic disease called congenital chloride-losing diarrhoea. The condition is caused by a single faulty gene that leaves carriers unable to absorb important ions like chloride into the cells of their intestines. It’s a problem that causes foetuses to be delivered prematurely and infants to be severely dehydrated.
This is the first time that a disease has been diagnosed based on sequencing a person’s genome, and it marks a dramatic first outing for a new genetic technology called “whole exome sequencing”, developed by Murim Choi and other Yale researchers.
Rather than sequencing the entire human genome, the new technique shines its spotlight only on the small proportion that contains genes that code for proteins. This so-called “exome” represents just 1% of our full set of DNA, but their minority status belies their true importance. Around 85% of the genetic changes that strongly affect our risk of diseases are found within these sequences. Focusing on the exome could be an efficient strategy for finding new variants linked to diseases or diagnosing genetic disorders, not least because our current knowledge of sequences that don’t code for proteins is relatively limited.
When Choi’s team received Baby T’s blood sample, they analysed it using their new method. They found that he carried two copies of the same sequences across substantial swathes of his genome, which you’d expect given his closely related parents. The team reasoned that the within these pairs lay the mutation that was causing the baby’s condition. But how to hunt it down?
For a start, they looked for sequences within these genes where Baby T differed from that of the standard human genome by a single base pair (a DNA ‘letter’). They found around 1,500 of these. They then focused on letters that are the same whether you’re looking at the gene of a human or that of a fly. These are called “conserved” sequences and their persistence over the course of evolution shows that they can’t be tinkered with without disrupting something critical.
By this point, they had focused their search so tightly that one mutation stood out like a beacon – a single change in a gene with the snappy name of SLC26A3. The mutation in question alters the gene at a place that is exactly the same in the genomes of humans, cows, mice, chicken, frogs, flies and worms. Clearly, this is an important part of an important gene, and changing it wrecks the encoded protein. In humans, faulty copies of SLC26A3 cause congenital chloride-losing diarrhoea (CLD), a condition that fit with all of Baby T’s symptoms.
The Turkish doctors were quick to confirm the diagnosis suggested by the exome sequencing. Their initial diagnosis – Bartter syndrome – is a kidney disease, but CLD affects the intestines. Indeed, a follow-up with Baby T showed that his dehydration came from losing water not from his kidneys, but from his gut in the form of diarrhoea. Second time round, the right disease had been identified.
The initial mistake was understandable for the two diseases present in a similar way. That became abundantly clear when Choi’s team screened 39 other patients with suspected Bartter syndrome, but who didn’t have any of the normal genetic markers for the disease. In fact, five of these people had CLD instead and all of them carried mutations in SLC26A3. One shared the same flaw that affected Baby T, while the others had different mutations that had never been seen before.
This story provides vivid evidence of the benefits of exome-sequencing in both diagnosis genetic diseases and identifying mutations that cause those diseases. In focusing on just 1% of the genome, it’s probably more efficient and Choi estimates that it’s 10-20 times cheaper than sequencing an entire genome. His team aren’t the only ones exploiting this technology. Just last month, a team of Seattle scientists found the gene behind a rare genetic disorder called Freeman-Sheldon syndrome by sequencing a dozen human exomes.
As Choi writes, “We can envision a future in which such information will become part of the routine clinical evaluation of patients with suspected genetic diseases in whom the diagnosis is uncertain.”
Reference: PNAS 10.1073/pnas.0910672106
More on genomics:
This is the eighth of eight posts on evolutionary research to celebrate Darwin’s bicentennial.
In Virginia, USA, sits a facility called the American Type Culture Collection. Within its four walls lie hundreds of freezers containing a variety of frozen biological samples and among these, are 99 strains of the common cold. These 99 samples represent all the known strains of the human rhinoviruses that cause colds. And all of their genomes have just been laid bare.
Ann Palmenberg from the University of Wisconsin and David Spiro from the J. Craig Venter Institute have cracked the genomes of all 99 strains, and used them to build a family tree that shows the relationships between them. Already, it has started to plug the holes in our understanding of this most common of infections. It reveals how different strains are related and how new strains evolve. It tells us which features are shared by all strains and which are the more unique traits that making rhinoviruses such slippery targets.
This extra knowledge may go some way to remedying the slightly baffling situation we find ourselves in, where all the vaunted progress of modern medicine has failed to produce a single approved treatment for an infection that most of us get at least twice a year.
The 99 historical strains of human rhinovirus fall into two separate species – HRV-A and HRV-B. More recently, a possible third species – HRV-C – has been identified in patients hospitalised with severe, flu-like illnesses. To build their family tree, Palmenberg and Spiro analysed the complete genomes of all 99 strains from the Virginia facility, seven samples of HRV-C, and 10 fresh samples collected from patients just a few years ago.